What was Barbara McClintock’s “mysticism”?

Or, how cells think and what life is

You ever go somewhere really, truly dark at night? You go outside, fighting the almost physical pain of not being able to see, and you look up: There is the Milky Way glowing in the sky, a galaxy spread above you. Maybe you glimpse the vastness of the universe for a second, or a minute, or until a twig snaps and you run inside.

I wish we had something like that for living things, some way to visualize the infinitude inside Mycoplasma genitalium or Zea mays or Homo sapiens.

Every single cell in the world is mind-bogglingly complex. About a decade ago, a team at Stanford led by Markus Covert created a simulation of a single M. genitalium cell. It required 900 scientific papers worth of data characterizing the bacterium, which is one of the simplest organisms known to science. The quote Covert gave to the New York Times has always stayed with me. “Right now, running a simulation for a single cell to divide only one time takes around 10 hours and generates half a gigabyte of data,” Dr. Covert said. “I find this fact completely fascinating, because I don’t know that anyone has ever asked how much data a living thing truly holds. We often think of the DNA as the storage medium, but clearly there is more to it than that.”

Covert’s team has been building a model to simulate one single E. coli cell since then. They have made huge progress, but they are still far from a complete model. In one paper, they compare modeling cells to modeling the weather… except the cells are tougher. Think about this: all of our biological research and computing technology and we still cannot comprehensively simulate one single cell of this model organism.

This fills me with awe, even a kind of terror. If every cell has that much going on, how should we approach even the tiniest plant?

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For weeks now, I’ve been reading books and papers about Barbara McClintock, famous for her study of maize chromosomes.¹ The outlines of her life are remarkable: she won a Nobel Prize in 1983, still the only woman to have won the physiology or medicine prize solo, and in a field (genetics) that is dominated by men. She never married or partnered, and maintained an image as a solitary figure interested exclusively in her plants. Here’s what fascinates me: both her critics and her fans often talk about her mysticism. How did a maize scientist acquire that aura?

McClintock was a throwback kind of geneticist. Right after she rose to prominence, the whole field got drunk on the discovery of DNA as the molecule that would reveal, or even was, the secret of life. It all seemed so … beautiful. Here was a molecule that could store information and transmit it across generations. A molecule that could act as a recipe book for all the proteins that an organism could need. The code was right there. All we had to do was learn to read it, and we would know the fundamental basis for life, evolution, development, all of it.

And with that swirling around her at Cold Spring Harbor Laboratory, McClintock was going out to the corn field at 6:30am to weed. She did not really deal in DNA, though she aware of the new discoveries. As a maize cytogeneticist, her core scientific practice involved breeding mutant corn plants and then looking at specially stained slides of their genetic material, searching for patterns. To recognize how difficult this was, this is what the 10 chromosomes of maize looked like under the microscope:

Through painstaking work, scientists like herself came to understand that some genetic factors were located in specific spots on particular chromosomes. And over time, McClintock came to recognize patterns in chromosomes broken at particular spots that corresponded to strange patterns in some corn leaves and kernels.

The language she used in her papers can be difficult to parse. And her work has also been successively reevaluated by decades of scientists, based on their understanding at the time. The basic story: she discovered transposable elements, parts of a genome that can move around, and that form the majority of the genome in maize and many other organisms. She didn’t get everything right, but it was a remarkable leap, and along a whole different dimension of genetics from the mainline of mid-century molecular biology.

What she saw, plant by plant, chromosome by chromosome, led her to believe that the neat story that the molecular guys were telling about how life worked was incomplete. The scientists of the time were aware that life was absurdly complicated, but reductive thinking about the molecular processes of cells was working. Few were interested in making things more difficult to understand.

Still, her observations could not be ignored. McClintock observed big chunks of chromosome 9 break off and fuse into a different part of a plant’s genome. How? She was seeing a genome that could *sense* problems in its chromosomes and attempt to fix them. Where was that in molecular biology’s models? This was revolutionary work, even if it could not be fully understood or explained by the field’s conceptual and technical tools.

“Her discovery of transposable elements in maize—so-called jumping genes—first presented in the early 1950s before her field had any language to express such a heterodox idea, was, in retrospect, the beginning of modern molecular genetics,” Stephen Jay Gould wrote in the New York Review of Books.

Whatever might be sitting there in the genetic sequence, the ATGCs, there were obviously many other mechanisms for making an organism’s life. Every layer of the plant—organism, cell, genome—seemed both incredibly competent and integrated.

Here we come to the core of what I think most people mean by McClintock’s “mysticism.” She had a remarkable respect for what organisms knew and could do, and not just those that were like humans. “You can't touch a plant without setting off an electric pulse... There is no question that plants have [all] kinds of sensitivities,” she told historian Evelyn Fox Keller. “They do a lot of responding to their environment. They can do almost anything you can think of. But just because they sit there, anybody walking down the road considers them just a plastic area to look at, [as if] they're not really alive.”

She had similar intuitions about what was happening at the microscopic level. She came to believe that cells, themselves, were remarkably good at accomplishing extremely complex tasks. “[Cells] make wise decisions and act upon them," she said in her 1983 Nobel lecture. “A goal for the future would be to determine the extent of knowledge the cell has of itself,” she went on, “and how it utilizes this knowledge in a ‘thoughtful’ manner when challenged.” Stop there for a second: knowledge the cell has of itself.

If a single cell can be conceptualized of as “thoughtful,” what might that say about a whole organism, plant, animal, or otherwise?

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“Many scientists have been upset because Barbara McClintock characterized herself as a mystic. But to her, mystic did not mean someone who mystifies,” wrote biologist James Shapiro, a McClintock acolyte and friend. “Instead, for Barbara McClintock, a mystic was someone with a deep awareness of the mysteries posed by natural phenomena. Mystification came, in her view, when we tried to use our current concepts to explain phenomena that demanded new ways of thinking.”

Biologists pretending they understood how the genome worked because they’d worked out some aspects of DNA, for example, was mystification in her sense.

“In its early days, molecular biology promised to provide us with an explanation of life in terms of physics and chemistry. However, since the 1960s, it has succeeded instead in amazing us with the richness and sophistication of intra- and intercellular control and communication networks,” Shapiro wrote in a book, Evolution: A View from the 21st Century.

Today, the basic story of a genome as a collection of DNA sequences (genes) that code for proteins is not untrue, but it’s also nowhere near a complete view. Life’s systems are dynamic and overlapping.

One example: The DNA in one human cell (with our relatively puny genome, relative to many plants and amphibians) would be something like 2 meters long, if you were to stretch it out base by base in sequence. But in reality, our genome folds up into this tiny space inside the nucleus, the equivalent of packing “a 24-mile long string into a tennis ball.” In recent years, biotechnologists have figured out how to get at these 3D structures in what is called Hi-C genomics. And it turns out that this topology affects the way the genome functions and genes are expressed.

Another: genomes turn out to be packed with all kinds of wild stuff, not just codes for genes. In maize, 85 perfect (!) of the genome is composed of the transposons that McClintock first discovered. Some researchers now describe all these different components as the “genomic ecosystem” of the plant. What does this say about evolution and domestication?

“McClintock thought of the genome as a complex unified system exquisitely integrated into the cell and the organism,” Shapiro wrote. He suggests that her view, and the evidence that has accumulated to support it, has pushed science away from thinking about the '“Constant Genome” and towards the “Fluid Genome,” a shift that hasn’t been metabolized fully by science or the public.

Returning to McClintock’s original question—what does a cell know of itself?—we could reframe the question, as biologist Dennis Bray does in his remarkable book, Wetware. We know from 150 years of the study of single-celled organisms that individual cells have remarkable capacities like tracking prey, or moving towards nutrients and away from toxins. So, we can ask, “How can a cell know anything?”

Bray makes a simple but comprehensive argument that proteins give cells the ability to work with information about their internal states and the external environment — and then take action based on that knowledge. Cells compute. “Protein molecules represent, in all their environment-tasting, message-generating, feature-extracting, memory-storing prodigality, what a cell knows of itself,” Bray writes.

All that complexity doessomething—it gives even the simplest living creatures the ability to make decisions. And that makes life fundamentally different from non-life.

I’ve been devouring the spectacular podcast Big Biology, and they’ve been circling the topics of life’s complexities and “agency” for a couple of years.² One of their foundational interviewees is Michael Levin, a distinguished biology professor at Tufts. Levin has developed a full-blown scientific framework and research agenda for investigating the cognitive capacities of living systems. He calls it: Technological Approach to Mind Everywhere. When Levin co-authored an essay with cognitive scientist Daniel Dennett, the excellent editors at Aeon Magazine gave it the title, “Cognition all the way down.” McClintock’s “thoughtful” cells would be right at home in their essay.

“We’re saying that biologists should chill out and see the virtues of anthropomorphising all sorts of living things,” write Levin and Dennett. If a living system has goals, as even the simplest clearly do, it is a mistake to pretend that it doesn’t. They warn that “teleophobia significantly holds back the ability to predict and control complex systems.”

So, what is Levin’s approach? He basically says: every level of biology has certain capacities to solve problems at its own scale. No, a cell doesn’t “think” like a human, but it can process information and take action in ways that are relevant to its environment.

Multicellular organisms absorb cells’ remarkable competence, but extend their goals over longer distances and time scales. “[W]hen cells join into an electrochemical network, they can now sense events, and act, on a much larger physical ‘radius of concern’ than a single cell. Moreover, the network can now integrate information coming from spatially disparate regions in complex ways that result in activity in other spatial regions,” Levin writes. “[T]he network has much more computational power than any of its individual cells (nodes), providing an IQ boost for the newly formed Self.”

In a more complex organism, the larger levels can shape what the lower levels perceive and thereby shape what they do. Organs figure out how to do their jobs by getting tissues to do the right thing. Tissues exert influence on the cells within them. And cells work with the biochemical networks they contain. These are complex interactions, of course, feeding back and forth.

Levin’s framework routes around some of the more annoying ways of thinking about thinking. There is no bright line that says “this is real thinking” and “this is not real thinking.” Rather, cognition exists on an evolved continuum. “[A]dvanced minds are in important ways generated in a continuous manner from much more humble proto-cognitive systems,” Levin writes. He points to the field of “basal cognition” as one that’s found “novel kinds of intelligences in single cells, plants, animal tissues, and swarms.”

This is really a complete inversion of the anthropomorphism debate. “We should seek ways to naturalize human capacities as elaborations of more fundamental principles that are widely present in complex systems, in very different types and degrees, and to identify the correct level for any given system,” Levin writes.

Take our brains, for example, with their neurons. For Levin, the use of electricity to carry information is not exclusive to brains. That’s not a philosophical stance, so much as an empirical one. Bioelectricity, as McClintock noted, is a pervasive phenomenon across kingdoms of life. “The unique computational capabilities of bioelectric circuits likely enabled the evolution of nervous systems, as specialized adaptations of the ancient ability of all cell networks to process electrical information as pre-neural networks,” Levin writes. The brain’s special feature is not the ability to store or spread information, but its speed. Let’s recall the old saw: “Plants are just very slow animals.” And then consider that it might be actually true.

Given all this, it’s actually not mystical at all to think about plant-fungus interchanges or ant colony psychology or cellular cognition in a protist or that we contain multitudes of other species. Plant decision-making isn’t some exotic phenomena, but rather an expected and researchable part of a world where organisms possess many different capabilities for processing information.

Of course a cell would have the means to repair its genome. Of course individual corn plants would respond to stimuli with bioelectric communication.

I can’t stop thinking about Levin’s framework and Bray’s wetware. We are assemblages of cooperating cells and tissues, each unit of life competent within the spaces our body creates. Trillions of brilliant little cells each doing its thing to make … me. I’m held together by bioelectric fields and metabolic processes and the convenient sense that I am a single being. At my own scale, I am a galaxy of sorts, hiding in plain sight, obscured by the bright sun of consciousness. And so are you.

Or, as McClintock told her biographer, “Basically, everything is one. There is no way in which you draw a line between things.”

Cuttings

There’s a beautiful new film, In the Clear Stream of All Of It, playing at the Roxie on September 9th. I’ll be doing a Q&A with the director Ben Grossman and producer Caitlyn Galloway. Get your tickets! It’s about Little City Farms in San Francisco, but it’s also about the cities we long for and lose and find.

“Once you really see one plant’s seed, you begin to see seed everywhere.” Exciting new book coming out: What We Sow: On the Personal, Ecological, and Cultural Significance of Seeds. Author Jennifer Jewell will be at Mrs. Dalloway’s in Berkeley on September 19th.

Earthling.fyi is hosting an experimental listening party in Golden Gate Park on September 17th.

A mini annotated bibliography. The classic biography A Feeling for the Organism by Evelyn Fox Keller is a good place to start. Nathaniel Comfort’s The Tangled Field attempts a revision and something of a downgrade of her legacy, I would say. It’s worth checking out Nina Fedoroff’s “McClintock’s Challenge in the 21st Century.” Her Times obituary. Stephen Jay Gould on McClintock in the NYRB. Jennifer Doudna of CRISPR fame has an interesting perspective, too. French biologist Christian Biémont provides an approachable walk-up on the science of transposable elements and McClintock’s importance. And of all of McClintock’s acolytes, I think the University of Chicago’s James Shapiro has been the best at developing precisely why her work is so significant. See, for example, “The discovery and significance of mobile genetic elements” from 1995, or his obituary for her.

Check out Big Biology’s breathtaking 100th episode, which pulls together a couple dozen interviews around the topic of “agency” in biology. This newsletter would not really be possible without all the thinking that Big Biology has presented. I’ve been marinating in their way of thinking about evolutionary biology for many weeks now.

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